Malignant female genital tract smooth muscle tumors with adipocytic differentiation: A morphologic, immunohistochemical, MDM2 fluorescence in situ hybridization and molecular genetic study of 6 lipoleiomyosarcomas.

Leiomyosarcoma with adipocytic differentiation or lipoleiomyosarcoma is an uncommon sarcoma of the female genital tract with only a few individual reports in the literature. We therefore performed a morphologic, immunohistochemical, MDM2 gene amplification and RNA and DNA sequencing analysis of a series of gynecologic lipoleiomyosarcoma to better define the clinicopathologic spectrum. Six tumors from 6 patients were identified and classified as spindled lipoleiomyosarcoma (n = 2), mixed spindled and myxoid lipoleiomyosarcoma (n = 1), epithelioid lipoleiomyosarcoma with focal myxoid features (n = 1) and mixed spindled and epithelioid lipoleiomyosarcoma (n = 2). Patient age ranged from 41 to 64 years (mean: 49; median: 50). Primary location included uterine corpus (3), uterine corpus/cervix (2) and broad ligament (1). Tumor size ranged from 4.5 to 22 cm (mean: 11.2; median: 9.8). Four patients had metastasis at presentation or subsequently developed recurrent or distant disease. Patient status was known for 5: 2 dead of disease, 2 alive with disease and 1 alive without evidence of disease. Immunohistochemical expression of smooth muscle markers, ER, PR and WT-1 showed patterns similar to non-adipocytic gynecologic leiomyosarcomas. MDM2 amplification fluorescence in situ hybridization performed on 2 tumors was negative in 1 and equivocal in 1. Sequencing studies performed on 3 tumors found TP53 mutations in 3, with 1 tumor also having an ATRX alteration. No gene fusions were identified. Although lipoleiomyosarcomas have a diverse morphologic spectrum, our findings suggest the smooth muscle component shares morphologic and immunohistochemical features with female genital tract non-adipocytic leiomyosarcomas. Lipoleiomyosarcomas also have genetic alterations associated with non-adipocytic gynecologic leiomyosarcomas.

Benign female genital tract smooth muscle tumors with adipocytic differentiation: A morphologic, immunohistochemical and MDM2 fluorescence in situ hybridization study of 44 conventional lipoleiomyomas and lipoleiomyoma variants.

Leiomyomas with adipocytic differentiation typically occur in the uterus although they may arise at several sites in the female genital tract. While these are most commonly spindled leiomyomas with a component of adipocytic tissue ("conventional lipoleiomyomas"), there is a relatively ill-defined assortment of leiomyoma variants with adipocytic differentiation. We performed a morphologic, immunohistochemical and MDM2 gene amplification analysis of a large series of gynecologic leiomyomas with adipocytic differentiation to better define the clinicopathologic spectrum. Forty four tumors from 44 patients were identified and classified as conventional lipoleiomyoma (n = 21), adipocyte-rich lipoleiomyoma (defined as tumor volume >80 % adipocytes, n = 9); cellular lipoleiomyoma (n = 9); hydropic lipoleiomyoma (n = 3); and lipoleiomyoma with bizarre nuclei (n = 2). Patient age ranged from 32 to 83 years (mean 63; median 63). Primary location included uterine corpus (35), uterine cervix (3), uterine corpus/cervix (1), broad ligament (2), parametrium (2), and round ligament (1). Tumor size was 0.6-30 cm (mean 8; median 6). None of the 34 patients with follow up developed further disease (range 1-311 months; mean 65; median 41). Immunohistochemical expression of ER, PR, HMB45, Melan A, Cathepsin K and WT-1 in lipoleiomyomas and variants was similar to patterns in non-adipocytic gynecologic leiomyomas. MDM2 amplification fluorescence in situ hybridization performed on 14 tumors was negative in all. Our findings suggest female genital tract conventional lipoleiomyomas and lipoleiomyoma variants largely parallel their non-adipocytic counterparts in morphology and immunophenotype, and may be categorized using non-adipocytic leiomyoma histologic criteria.

Mohs surgery for female genital Paget's disease: a prospective observational trial.

BACKGROUND: Extramammary Paget's disease recurs often after traditional surgical excision. Margin-controlled surgery improves the recurrence rate for male genital disease but is less studied for female anatomy. OBJECTIVE: This study aimed to compare surgical and oncologic outcomes of margin-controlled surgery vs traditional surgical excision for female genital Paget's disease. STUDY DESIGN: We conducted a prospective observational trial of patients with vulvar or perianal Paget's disease treated with surgical excision guided by Mohs micrographic surgery between 2018 and 2022. The multidisciplinary protocol consisted of office-based scouting biopsies and modified Mohs surgery followed by surgical excision with wound closure under general anesthesia. Modified Mohs surgery cleared peripheral disease margins using a moat technique with cytokeratin 7 staining. Medial disease margins (the clitoris, urethra, vagina, and anus) were assessed using a hybrid of Mohs surgery and intraoperative frozen sections. Surgical and oncologic outcomes were compared with the outcomes of a retrospective cohort of patients who underwent traditional surgical excision. The primary outcome was 3-year recurrence-free survival. RESULTS: Three-year recurrence-free survival was 93.3% for Mohs-guided excision (n=24; 95% confidence interval, 81.5%-100.0%) compared to 65.9% for traditional excision (n=63; 95% confidence interval, 54.2%-80.0%) (P=.04). The maximum diameter of the excisional specimen was similar between groups (median, 11.3 vs 9.5 cm; P=.17), but complex reconstructive procedures were more common with the Mohs-guided approach (66.7% vs 30.2%; P<.01). Peripheral margin clearance was universally achieved with modified Mohs surgery, but positive medial margins were noted in 9 patients. Reasons included intentional organ sparing and poor performance of intraoperative hematoxylin and eosin frozen sections without cytokeratin 7. Grade 3 or higher postoperative complications were rare (0.0% for Mohs-guided excision vs 2.4% for traditional excision; P=.99). CONCLUSION: Margin control with modified Mohs surgery significantly improved short-term recurrence-free survival after surgical excision for female genital Paget's disease. Use on medial anatomic structures (the clitoris, urethra, vagina, and anus) is challenging, and further optimization is needed for margin control in these areas. Mohs-guided surgical excision requires specialized, collaborative care and may be best accomplished at designated referral centers.

Frequency of HER2 protein overexpression and HER2 gene amplification in endometrial clear cell carcinoma.

HER2 (ERBB2) overexpression and/or HER2 gene amplification has been well established in several tumors types and when present HER2 directed therapy may be to be efficacious. While recent findings suggests that HER2 overexpression and HER2 amplification are a relatively common in serous endometrial carcinoma, similar data regarding clear cell endometrial carcinoma (CCC) is difficult to interpret due to issues such as diagnostic criteria, sample type and HER2 interpretation criteria. Our goals were to study HER2 expression and HER2 copy number status in hysterectomy specimens from a large series of patients with pure CCC to determine the frequency of HER2 overexpression and HER2 amplification and evaluate applicability of current HER2 interpretation criteria. Pure CCC specimens derived from hysterectomy specimens from 26 patients were identified. All diagnoses were confirmed by two gynecologic pathologists. Immunohistochemistry for HER2 protein and fluorescence in situ hybridization (FISH) studies for HER2 were performed on whole-slide sections from all cases. Results were interpreted according to the 2018 ASO/CAP HER2 guidelines for breast cancer and International Society of Gynecologic Pathologists (ISGyP) HER2 guidelines for serous endometrial carcinoma. Additional testing was performed when indicated by the guidelines. HER2 expression by immunohistochemistry was 3+ in 4% and 0% of cases, and 2+ in 46% and 52% of cases, by 2018 ASCO/CAP and ISGyP criteria, respectively, while the remaining cases were negative. HER2 testing by FISH showed a positive result in 27% of tumors with 2018 ASCO/CAP guidelines, while 23% were positive with the ISGyP criteria. Our findings indicate that HER2 overexpression and HER2 amplification occur in a subset of CCC. Therefore, additional study into the potential benefit of HER2 targeted therapy in patients with CCC is warranted.

Single patch super-resolution of histopathology whole slide images: a comparative study.

Purpose: The latest generation of scanners can digitize histopathology glass slides for computerized image analysis. These images contain valuable information for diagnostic and prognostic purposes. Consequently, the availability of high digital magnifications like 20 × and 40 × is commonly expected in scanning the slides. Thus, the image acquisition typically generates gigapixel high-resolution images, times as large as 100,000 × 100,000 pixels . Naturally, the storage and processing of such huge files may be subject to severe computational bottlenecks. As a result, the need for techniques that can operate on lower magnification levels but produce results on par with outcomes for high magnification levels is becoming urgent. Approach: Over the past decade, the digital solution of enhancing images resolution has been addressed by the concept of super resolution (SR). In addition, deep learning has offered state-of-the-art results for increasing the image resolution after acquisition. In this study, multiple deep learning networks designed for image SR are trained and assessed for the histopathology domain. Results: We report quantitative and qualitative comparisons of the results using publicly available cancer images to shed light on the benefits and challenges of deep learning for extrapolating image resolution in histopathology. Three pathologists evaluated the results to assess the quality and diagnostic value of generated SR images. Conclusions: Pixel-level information, including structures and textures in histopathology images, are learnable by deep networks; hence improving the resolution quantity of scanned slides is possible by training appropriate networks. Different SR networks may perform best for various cancer sites and subtypes.

Into the future: A pilot study combining imaging with molecular profiling to predict resectability in ovarian cancer.

OBJECTIVE: We sought to determine the predictive value of combining tumor molecular subtype and computerized tomography (CT) imaging for surgical outcomes after primary cytoreductive surgery in advanced stage high-grade serous ovarian cancer (HGSOC) patients. METHODS: We identified 129 HGSOC patients who underwent pre-operative CT imaging and post-operative tumor mRNA profiling. A continuous CT-score indicative of overall disease burden was defined based on six imaging measurements of anatomic involvement. Molecular subtypes were derived from mRNA profiling of chemo-naïve tumors and classified as mesenchymal (MES) subtype (36%) or non-MES subtype (64%). Fischer exact tests and multivariate logistic regression examined residual disease and surgical complexity. RESULTS: Women with higher CT-scores were more likely to have MES subtype tumors (p = 0.014). MES subtypes and a high CT-score were independently predictive of macroscopic disease and high surgical complexity. In multivariate models adjusting for age, stage and American Society of Anesthesiologists (ASA) score, patients with a MES subtype and high CT-score had significantly elevated risk of macroscopic disease (OR = 26.7, 95% CI = [6.42, 187]) and were more likely to undergo high complexity surgery (OR = 9.53, 95% CI = [2.76, 40.6], compared to patients with non-MES tumor and low CT-score. CONCLUSION: Preoperative CT imaging combined with tumor molecular subtyping can identify a subset of women unlikely to have resectable disease and likely to require high complexity surgery. Along with other clinical factors, these may refine predictive scores for resection and assist treatment planning. Investigating methods for pre-surgical molecular subtyping is an important next step.

A diagnostic approach to paratesticular lesions with tubulopapillary architecture: a series of 16 serous borderline tumors/low-grade serous carcinoma and 14 well-differentiated papillary mesothelial tumors and mesothelioma.

As there is limited literature on paratesticular tumors of müllerian and mesothelial origin, we reviewed archived cases of serous borderline tumors (n = 15), low-grade serous carcinoma (n = 1), well-differentiated papillary mesothelial tumors (WDPMTs; n = 2), and mesothelioma (n = 12), for relevant clinicopathologic features. Molecular profiling data from the American Association for Cancer Research (AACR) GENIE registry was accessed for 8 additional patients with testicular mesothelioma. For tumors of mesothelial origin, the median age at surgical excision was 62 years, the median size was 4.5 cm, and they consistently exhibited positivity for mesothelial markers (CK5/6, calretinin, WT1, and D2-40). Recurrent alterations of the NF2 gene were identified in 3 of 8 patients (38%), and alterations of BAP1 and CDKN2A were relatively infrequent. While one patient with WDPMT had a recurrence, a second patient with WDPMT progressed to a biphasic mesothelioma 2 years after initial resection. For tumors of müllerian origin, the median age at surgical excision was 45 years, the median size was 2.5 cm, and these exhibited consistent positivity for ER, WT1, and PAX8. Although no recurrences were documented in patients with serous borderline tumors, a single patient with a low-grade serous carcinoma developed widely metastatic disease and died of disease-related complications. Our study emphasizes the need for close clinical follow-up in patients with WDPMT and highlights the prognostic significance of documenting invasive behavior in tumors of müllerian origin as they can have an aggressive clinical course. Finally, our results suggest that NF2 alterations may play an important role in the pathogenesis of testicular mesothelioma.

Ultrastaging of 'negative' pelvic lymph nodes in patients with low- and intermediate-risk endometrioid endometrial cancer who developed non-vaginal recurrences.

OBJECTIVE: Evidence on micrometastases and isolated tumor cells as factors associated with non-vaginal recurrence in low- and intermediate-risk endometrial cancer is limited. The goal of our study was to investigate risk factors for non-vaginal recurrence in low- and intermediate-risk endometrial cancer. METHODS: Records of all patients with endometrial cancer surgically managed at the Mayo Clinic before sentinel lymph node implementation (1999-2008) were reviewed. We identified all patients with endometrioid low-risk (International Federation of Gynecology and Obstetrics (FIGO) stage I, grade 1 or 2 with myometrial invasion <50% and negative peritoneal cytology) or intermediate-risk (FIGO stage I, grade 1 or 2 with myometrial invasion ≥50% or grade 3 with myometrial invasion <50% and negative peritoneal cytology) endometrial cancer at definitive pathology after pelvic and para-aortic lymph node assessment. All pelvic lymph nodes of patients with non-vaginal recurrence (any recurrence excluding isolated vaginal cuff recurrences) underwent ultrastaging. RESULTS: Among 1303 women, we identified 321 patients with low-risk (n=236) or intermediate-risk (n=85) endometrial cancer (median age 65.4 years; 266 (82.9%) stage IA; 55 (17.1%) stage IB). Of the total of 321, 13 patients developed non-vaginal recurrence (Kaplan-Meier rate 4.7% by 60 months; 95% CI 2.1% to 7.2%): 11 hematogenous/peritoneal and two para-aortic and distant lymphatic. Myometrial invasion and lymphovascular space invasion were univariately associated with non-vaginal recurrence. In these patients, the original hematoxylin/eosin slides review confirmed all 646 pelvic and para-aortic removed lymph nodes as negative. The ultrastaging of 463 pelvic lymph nodes did not identify any occult metastases (prevalence 0%; 95% CI 0% to 22.8% considering 13 patients; 95% CI 0% to 0.8% considering 463 pelvic lymph nodes). CONCLUSION: There were no occult metastases in pelvic lymph nodes of patients with low- or intermediate-risk endometrial cancer with non-vaginal recurrence. Myometrial invasion and lymphovascular space invasion appear to be associated with non-vaginal recurrence.

Tao brush endometrial cytology is a sensitive diagnostic tool for cancer and hyperplasia among women presenting to clinic with abnormal uterine bleeding.

BACKGROUND: Abnormal uterine bleeding requires the investigation of the endometrium. Histology is typically used but there remains room for the improvement and use of cytology. METHODS: Women presenting for clinically indicated office endometrial biopsy were prospectively enrolled. Tao endometrial brushing and office endometrial biopsy were performed, and surgical procedure if clinically indicated. Tao brush cytology specimens were blindly reviewed by up to three pathologists, consensus obtained, and scored as: benign, atypical (favor benign), suspicious, positive for malignancy, or non-diagnostic. Cytology and histology were compared to surgical pathology to determine sensitivity, specificity, positive, and negative predictive values to detect AH (atypical hyperplasia) or EC (endometrial cancer). RESULTS: Clinical indications of 197 enrolled patients included postmenopausal bleeding (90, 45.7%), abnormal uterine bleeding (94, 47.7%), and abnormal endometrium on ultrasound without bleeding (13, 6.6%). Of the 197 patients, 185 (93.9%) had cytology score consensus and a total of 196 (99.5%) had consensus regarding cytology positivity. Surgical pathology diagnoses (N = 85) were 13 (15.3%) FIGO grade 1 or 2 EC, 3 (3.5%) AH, and 69 (81.2%) benign endometrium. Sensitivity and specificity to detect EC or AH were 93.7% and 100%, respectively, via endometrial biopsy; 87.5% and 63.8%, respectively, via endometrial cytology when scores of malignancy, suspicious, or atypical were considered positive. CONCLUSIONS: In a high-risk population, Tao brush endometrial cytology showed high sensitivity to detect AH and EC comparable to biopsy histology when considering scores of malignancy, suspicious, atypical, and non-diagnostic. Revisiting the potential value of endometrial cytology in the contemporary era of endometrial diagnostic workup is warranted.

In search for biomarkers and potential drug targets for uterine serous endometrial cancer.

OBJECTIVE: Serous endometrial cancer (USC) is a challenging malignancy associated with metastasis, recurrence and poor outcome. To identify clinically relevant prognostic biomarkers, we focused on a panel of proteins selected after a comprehensive literature review, for tumour profiling of a homogeneous cohort of USC patients. METHODS: Protein levels and localization were assessed by immunohistochemistry analysis in 36 hysterectomy samples. Tissue sections were stained with the following antibodies: Aurora A, phospho (T288) Aurora A, BRCA1, CHK1, CIP2A, Cyclin B1, Cyclin E, E2F-1, phospho (S364) E2F-1, FBXW7, FOXM1, phospho (S9) GSK3Beta, PLK1, phospho (T210) PLK1, PPP2R1B, p73, RAD51. Each marker was evaluated as a continuously-scaled variable for association with disease progression and death, using Cox proportional hazards models. The sample consisted of 36 patients with USC, half with stage III or IV disease. RESULTS: Results showed that higher CHK1 (Checkpoint kinase 1) expression was associated with a decreased risk of progression and death, after adjusting for stage. Interestingly, analysis of a TCGA data set of 109 USC patients corroborates our results showing a favourable prognostic role of CHEK1 after adjusting for stage. Higher FBXW7 (F-box and WD repeat domain containing 7) expression and higher cytoplasmic expression of PPP2R1B (Protein Phosphatase 2 A, Scaffold Subunit Abeta) were each associated with a decreased risk of progression, after adjusting for stage. CONCLUSIONS: In conclusion, results from the present study identify new clinically relevant biomarkers and potential drug targets for uterine serous endometrial cancer.

Adjuvant brachytherapy for FIGO stage I serous or clear cell endometrial cancer.

OBJECTIVES: Optimal adjuvant treatment for early-stage clear cell and serous endometrial cancer remains unclear. We report outcomes for women with surgically staged International Federation of Gynecology and Obstetrics (FIGO) stage I clear cell, serous, and mixed endometrial cancers following adjuvant vaginal cuff brachytherapy with or without chemotherapy. METHODS: From April 1998 to January 2020, women with FIGO stage IA-IB clear cell, serous, and mixed endometrial cancer underwent surgery and adjuvant vaginal cuff brachytherapy. Seventy-six patients received chemotherapy. High-dose rate vaginal cuff brachytherapy was planned to a total dose of 21 gray in three fractions using a multichannel vaginal cylinder. The primary objective was to determine the effectiveness of adjuvant vaginal cuff brachytherapy and to identify surgicopathological risk factors that could portend towards worse oncological outcomes. RESULTS: A total of 182 patients were included in the analysis. Median follow-up was 5.3 years (2.3-12.2). Ten-year survival was 73.3%. Five-year cumulative incidence (CI) of vaginal, pelvic, and para-aortic relapse was 1.4%, 2.1%, and 0.9%, respectively. Five-year locoregional failure, any recurrence, peritoneal relapse, and other distant recurrence was 4.4%, 11.6%, 5.3%, and 6.7%, respectively. On univariate analysis, locoregional failure was worse for larger tumors (per 1 cm) (HR 1.9, 95% CI 1.2 to 3.0, p≤0.01). Any recurrence was worse for tumors of at least 3.5 cm (HR 3.8, 95% CI 1.3 to 11.7, p=0.02) and patients with positive/suspicious cytology (HR 4.4, 95% CI 1.5 to 12.4, p≤0.01). Ten-year survival for tumors of at least 3.5 cm was 56.9% versus 86.6% for those with smaller tumors (HR 2.9, 95% CI 1.4 to 5.8, p≤0.01). Ten-year survival for positive/suspicious cytology was 50.9% versus 77.4% (HR 2.2, 95% CI 0.9 to 5.4, p=0.09). Multivariate modeling demonstrated worse locoregional failure, any recurrence, and survival with larger tumors, as well as any recurrence with positive/suspicious cytology. Subgroup analysis demonstrated improved outcomes with the use of adjuvant chemotherapy in patients with large tumors or positive/suspicious cytology. CONCLUSION: Adjuvant vaginal cuff brachytherapy alone without chemotherapy is an appropriate treatment for women with negative peritoneal cytology and small, early-stage clear cell, serous, and mixed endometrial cancer. Larger tumors or positive/suspicious cytology are at increased risk for relapse and worse survival, and should be considered for additional upfront adjuvant treatments, such as platinum-based chemotherapy.

Role of adjuvant therapy in stage IIIC2 endometrial cancer.

OBJECTIVE: The role of the different types of adjuvant treatments in endometrial cancer with para-aortic node metastases is unclear. The aim of this study was to report oncologic outcomes after adjuvant therapy in patients with stage IIIC2 endometrial cancer. METHODS: This retrospective single-institution study assessed patients with stage IIIC2 endometrial cancer who underwent primary surgery from January 1984 to December 2014. All patients had hysterectomy (±salpingo-oophorectomy) plus lymphadenectomy (para-aortic nodes, ±pelvic nodes). We included all patients with stage III endometrial cancer and documented para-aortic lymph node metastases (International Federation of Obstetrics and Gynecologists stage IIIC2). We excluded patients who did not provide consent, who had synchronous cancer, or who underwent neoadjuvant chemotherapy. Follow-up was restricted to the first 5 years post-operatively. Cox proportional hazards models, with age as the time scale, was used to evaluate associations of risk factors with disease-free survival and overall survival. RESULTS: Among 105 patients with documented adjuvant therapy, external beam radiotherapy was administered to 25 patients (24%), chemotherapy to 24 (23%), and a combination (chemotherapy and external beam radiotherapy) to 56 (53%) patients. Most patients receiving chemotherapy and external beam radiotherapy (80%) had chemotherapy first. The majority of relapses had a distant component (31/46, 67%) and only one patient had an isolated para-aortic recurrence. Non-endometrioid subtypes had poorer disease-free survival (HR 2.57; 95% CI 1.38 to 4.78) and poorer overall survival (HR 2.00; 95% CI 1.09 to 3.65) compared with endometrioid. Among patients with endometrioid histology (n=60), chemotherapy and external beam radiotherapy improved disease-free survival (HR 0.22; 95% CI 0.07 to 0.71) and overall survival (HR 0.28; 95% CI 0.09 to 0.89) compared with chemotherapy or external beam radiotherapy alone. Combination therapy did not improve prognosis for patients with non-endometrioid histology (n=45). CONCLUSIONS: In our cohort of patients with stage IIIC2 endometrioid endometrial cancer, those receiving chemotherapy and external beam radiotherapy had improved survival compared with patients receiving chemotherapy or external beam radiotherapy alone. However, the prognosis of patients with non-endometrioid endometrial cancer remained poor, regardless of the adjuvant therapy administered. Distant recurrences were the most common sites of failure.

Intraoperative Pathologic Margin Analysis and Re-Excision to Minimize Reoperation for Patients Undergoing Breast-Conserving Surgery.

BACKGROUND: Reoperation rates following breast-conserving surgery (BCS) range from 10 to 40%, with marked surgeon and institutional variation. OBJECTIVE: The aim of this study was to identify factors associated with intraoperative margin re-excision, evaluate for any differences in local recurrence based on margin re-excision and determine reoperation rates with use of intraoperative margin analysis. PATIENTS AND METHODS: We analyzed consecutive patients with ductal carcinoma in situ (DCIS) or invasive breast cancer who underwent BCS at our institution between 1 January 2005 and 31 December 2016. Routine intraoperative frozen section margin analysis was performed and positive or close margins were re-excised intraoperatively. Univariate analysis was used to compare margin status and the Kaplan-Meier method was used to compare recurrence. Multivariable logistic regression was utilized to analyze factors associated with re-excision. RESULTS: We identified 3201 patients who underwent BCS-688 for DCIS and 2513 for invasive carcinoma. Overall, 1513 (60.2%) patients with invasive cancer and 434 (63.1%) patients with DCIS had close or positive margins that underwent intraoperative re-excision. Margin re-excision was associated with larger tumor size in both groups. The permanent pathology positive margin rate among all patients was 1.2%, and the 30-day reoperation rate for positive margins was 1.1%. Five-year local recurrence rates were 0.6% and 1.2% for patients with DCIS and invasive cancer, respectively. There was no difference in recurrence between patients with and without intraoperative margin re-excision (p = 0.92). CONCLUSION: Both DCIS and invasive carcinoma had similar rates of intraoperative margin re-excision. Although intraoperative margin re-excision was common, the reoperation rate was extremely low and there was no difference in recurrence between those with or without intraoperative re-excision.

Uterine inflammatory myofibroblastic tumors in pregnant women with and without involvement of the placenta: a study of 6 cases with identification of a novel TIMP3-RET fusion.

Uterine inflammatory myofibroblastic tumors (IMTs) have been reported in association with pregnancy and, in some instances, secondarily involve the placenta. The clinicopathological spectrum of these tumors in the setting of pregnancy is not well defined. We investigated the clinical, morphologic, immunohistochemical, molecular cytogenetic, and genetic features of 6 uterine IMTs occurring in pregnant women. Each tumor was discovered at parturition, and none was identified by prenatal ultrasound. Patient age ranged from 25 to 41 years (mean 31.5). Tumor size ranged from 1.5 to 9 cm (mean 4.7). Four of 6 had usual IMT features, with at least focal deciduoid change in 3. Necrosis was identified in 3 tumors; and multinucleated cells, in 3 tumors. Sex hormone receptor expression was consistent with estrogen receptor negative or focally weakly positive and progesterone receptor diffusely moderately or moderately to strongly positive in all 6 tumors. ALK immunohistochemistry was strongly positive in 5 tumors, and all of these had an ALK rearrangement detected by break-apart fluorescence in situ hybridization. Subsequent RNA sequencing of these 5 tumors identified a TIMP3-ALK fusion in 4 and a THBS1-ALK in 1. In the ALK-negative tumor, RNA sequencing detected a novel TIMP3-RET fusion that was confirmed by RET break-apart fluorescence in situ hybridization. Follow-up was available for 2 of 6 patients 5 and 19 months after diagnosis. Neither patient developed recurrence. ALK immunohistochemistry will distinguish most uterine IMTs, but if ALK expression and gene studies are negative, in the appropriate morphologic context, evaluation of other tyrosine kinase genes known to be more commonly altered in extrauterine IMTs such as ROS1, NTRK3, PDGFRß, and RET may be necessary for diagnostic confirmation.

Role of lymphadenectomy in endometrial cancer with nonbulky lymph node metastasis: Comparison of comprehensive surgical staging and sentinel lymph node algorithm.

OBJECTIVES: To compare survival and progression outcomes between 2 nodal assessment approaches in patients with nonbulky stage IIIC endometrial cancer (EC). METHODS: Patients with stage IIIC EC treated at 2 institutions were retrospectively identified. At 1 institution, a historical series (2004-2008) was treated with systematic pelvic and para-aortic lymphadenectomy (LND cohort). At the other institution, more contemporary patients (2006-2013) were treated using a sentinel lymph node algorithm (SLN cohort). Outcomes (hazard ratios [HRs]) within the first 5 years after surgery were compared between cohorts using Cox models adjusted for type of adjuvant therapy. RESULTS: The study included 104 patients (48 LND, 56 SLN). The use of chemoradiotherapy was similar in the 2 cohorts (46% LND vs 50% SLN), but the use of chemotherapy alone (19% vs 36%) or radiotherapy alone (15% vs 2%) differed. Although there was evidence of higher risk of cause-specific death (HR, 2.10; 95% CI, 0.79-5.58; P = 0.14) and lower risk of para-aortic progression (HR, 0.27; 95% CI, 0.05-1.42; P = 0.12) for the LND group, the associations did not meet statistical significance. The risk of progression was not significantly different between the groups (HR, 1.27; 95% CI, 0.60-2.67; P =0 .53). In parsimonious multivariable models, high-risk tumor characteristics and nonendometrioid type were independently associated with lower cause-specific survival and progression-free survival. CONCLUSIONS: In EC patients with nonbulky positive lymph nodes, use of the SLN algorithm with limited nodal dissection does not compromise survival compared with LND. Aggressive pathologic features of the primary tumor are the strongest determinants of prognosis.

Sentinel lymph node biopsy with cervical injection of indocyanine green in apparent early-stage endometrial cancer: predictors of unsuccessful mapping.

OBJECTIVE: To identify predictors of unsuccessful sentinel lymph node (SLN) mapping in patients with apparent early-stage endometrial cancer (EC) undergoing surgical staging with cervical injection of indocyanine green and SLN biopsy. METHODS: We retrospectively identified consecutive patients with EC with attempted SLN biopsy between June 2014 and June 2016 at our institution. Patients were grouped according to whether they had a successful procedure, defined as the bilateral identification of SLNs, or an unsuccessful procedure, defined as unilateral or no SLN mapping. Logistic regression was used to evaluate predictors of an unsuccessful procedure. RESULTS: Among 327 patients included in the analysis, 256 (78.3%) had a successful procedure and 71 (21.7%) had an unsuccessful procedure (15.0% unilateral SLN mapping, 6.7% no mapping). The rate of successful procedure increased from 57.7% to 83.3% between the first and last quarters of the 2-year study period, which represented the learning curve for the technique. The mean (SD) operative time decreased from 164 (55) to 137 (37) minutes. By multivariable analysis, lysis of adhesions at the beginning of surgery (odds ratio, 3.07; 95% CI, 1.56-6.07) and the presence of enlarged lymph nodes (odds ratio, 4.69; 95% CI, 1.82-12.11) were independently associated with an unsuccessful procedure. CONCLUSIONS: Lysis of adhesions at the beginning of surgery and the presence of enlarged lymph nodes independently affect the bilateral detection of SLNs.

A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases.

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.

Ultrastaging of negative pelvic lymph nodes to decrease the true prevalence of isolated paraaortic dissemination in endometrial cancer.

OBJECTIVE: This study aimed to determine the prevalence of occult pelvic lymph node metastasis in patients with endometrial cancer (EC) with isolated paraaortic dissemination who underwent pelvic and paraaortic lymphadenectomy. METHODS: From 2004 to 2008, patients undergoing surgery for EC at our institution were prospectively treated according to a validated surgical algorithm relying on intraoperative frozen section. For the current study, we re-reviewed pathologic slides obtained at the time of diagnosis and performed ultrastaging of all negative pelvic lymph nodes to assess the prevalence of occult pelvic lymph node metastasis. RESULTS: Of 466 patients at risk for lymphatic dissemination, 394 (84.5%) underwent both pelvic and paraaortic lymphadenectomy. Of them, 10 (2.5%) had isolated paraaortic metastasis. Pathologic review of hematoxylin-eosin-stained slides identified 1 patient with micrometastasis in 1 of 18 pelvic lymph nodes removed. Ultrastaging of 296 pelvic lymph nodes removed from the 9 other patients (median [range], 32 [20-50] nodes per patient) identified 2 additional cases (1 with micrometastasis and 1 with isolated tumor cells), for a total of 3/10 patients (30%) having occult pelvic dissemination. CONCLUSIONS: Ultrastaging and pathologic review of negative pelvic lymph nodes of patients with presumed isolated paraaortic metastasis can identify occult pelvic dissemination and reduce the prevalence of true isolated paraaortic disease. In the era of the sentinel lymph node (SLN) algorithm for EC staging, which incorporates ultrastaging of the SLNs removed, these findings demonstrate that use of the SLN algorithm can further mitigate the concern of missing cases of isolated paraaortic dissemination.

Uterine serous carcinoma: Reassessing effectiveness of platinum-based adjuvant therapy.

OBJECTIVE: Two randomized trials failed to demonstrate efficacy of platinum-based chemotherapy (PbCT) for uterine serous carcinoma (USC). Our objective was to reassess the value of PbCT for patients with microscopic residuum (R0). METHODS: Progression-free survival (PFS) after surgery was analyzed for 409 patients and correlated with adjuvant therapies: vaginal brachytherapy (VBRT), external beam radiotherapy (EBRT), PbCT, or combinations. RESULTS: The estimated 5-year PFS for stage I (n=209) USC was 65.1% for observation only; 90.7%, VBRT only; and 91.1%, PbCT±VBRT (85% received VBRT); VBRT significantly (P=.004) impacted PFS, but the added value of PbCT remains uncertain. Of 58 stage IIIC, PbCT-treated patients (±EBRT), 5-year PFS was 33.9%; most failures had a vascular disseminated component. Median PFS for 72 stage IV, PbCT-treated patients was 18.6months for R0; 8.0, R1≤1cm residual disease; and 4.6, R2>1cm (P=.008). The progression rate (PR) during 1 to 2year follow-up for R0 was similar to PR during 0-1year follow-up for R1 (P=.31), suggesting recurrences in patients with R0 disease before 2years are likely platinum resistant. PRs during follow-up were nearly identical for R0≥2years and R1≥1year (P=.95), presumably showing limited numbers of platinum-sensitive tumors. CONCLUSIONS: A comparison of PR for patients treated with PbCT for stage IV R0 and R1 disease suggested that a 1-year lag interval precedes clinical recognition of PbCT refractory/resistant R0 disease. Most patients treated with PbCT who had microscopic residuum had recurrences within 2years (across stages), emphasizing the need for more effective therapy.